CN106187862A - 一种1‑叔丁氧羰基哌啶‑4‑甲醛的制备方法 - Google Patents
一种1‑叔丁氧羰基哌啶‑4‑甲醛的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 title abstract description 8
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 title abstract 3
- 239000000203 mixture Substances 0.000 claims abstract description 34
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- OQVYMXCRDHDTTH-UHFFFAOYSA-N 4-(diethoxyphosphorylmethyl)-2-[4-(diethoxyphosphorylmethyl)pyridin-2-yl]pyridine Chemical group CCOP(=O)(OCC)CC1=CC=NC(C=2N=CC=C(CP(=O)(OCC)OCC)C=2)=C1 OQVYMXCRDHDTTH-UHFFFAOYSA-N 0.000 claims abstract description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims abstract description 3
- 239000012467 final product Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- JYUQEWCJWDGCRX-UHFFFAOYSA-N tert-butyl 4-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)CC1 JYUQEWCJWDGCRX-UHFFFAOYSA-N 0.000 claims description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 17
- 208000035126 Facies Diseases 0.000 claims description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000008346 aqueous phase Substances 0.000 claims description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 7
- 239000012141 concentrate Substances 0.000 claims description 6
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- 238000004809 thin layer chromatography Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical group CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 10
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 abstract description 9
- -1 tertbutyloxycarbonyl 4 piperidine Chemical compound 0.000 abstract description 5
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 238000009434 installation Methods 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 3
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- VUZNLSBZRVZGIK-UHFFFAOYSA-N 2,2,6,6-Tetramethyl-1-piperidinol Chemical group CC1(C)CCCC(C)(C)N1O VUZNLSBZRVZGIK-UHFFFAOYSA-N 0.000 abstract 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000013517 stratification Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241001122315 Polites Species 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 description 2
- 229960003135 donepezil hydrochloride Drugs 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical group CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
- B01J31/32—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of manganese, technetium or rhenium
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/19—Catalysts containing parts with different compositions
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/16—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
- B01J23/32—Manganese, technetium or rhenium
- B01J23/34—Manganese
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种1‑叔丁氧羰基哌啶‑4‑甲醛的制备方法，包括下列步骤：1)将1‑叔丁氧羰基‑4‑哌啶甲醇、有机溶剂与水混合得混合物A；2)将混合物A降温至5℃以下，加入催化剂、助催化剂和碳酸氢钠，得混合物B；所述催化剂为2,2,6,6‑四甲基哌啶氧化物；助催化剂为锰酸钾；3)将混合物B降温至0℃以下，加入NaClO进行氧化反应，后分离纯化即得。本发明的1‑叔丁氧羰基哌啶‑4‑甲醛的制备方法，所用的TEMPO‑K2MnO4催化体系催化活性高、效果好、产物收率高；该方法具有操作简便、反应条件温和、易于控制、设备利用率高等优点，适合大规模工业化生产。
Description
技术领域
本发明属于有机化学合成技术领域，具体涉及1-叔丁氧羰基哌啶-4-甲醛的制备方法。
背景技术
盐酸多奈哌齐是由日本卫材制药公司开发的乙酰胆碱酯酶抑制剂(AchEI)，主要成分是(±)2,3-双羟基-5,6-双甲氧基-2-{1-(苯甲基)-4-哌啶基甲基}-1H-茚-1-酮盐酸盐，1997年首次在美国上市，该品对神经元乙酰胆碱酯酶具有高度选择性，无肝脏毒性，临床用于治疗阿尔茨海默病。1-叔丁氧羰基哌啶-4-甲醛作为合成盐酸多奈哌齐的重要中间体，其制备和产量直接影响盐酸多奈哌齐的生产，因此，近年来1-叔丁氧羰基哌啶-4-甲醛的制备及研究工作受到越来越广泛的关注。
目前，合成1-叔丁氧羰基哌啶-4-甲醛主要采用斯文氧化反应(SwernOxidation)，斯文氧化反应是利用二甲基亚砜(DMSO)作氧化剂和有机碱(如三乙胺)在低温下与草酰氯协同作用，将一级醇或二级醇氧化成醛或酮的反应。但是，该反应合成1-叔丁氧羰基哌啶-4-甲醛需要在-78℃下进行，反应条件苛刻，设备利用率低，不适合工业化大规模生产，因此急需对其制备方法进行改进。
发明内容
本发明的目的是提供一种1-叔丁氧羰基哌啶-4-甲醛的制备方法。
为了实现以上目的，本发明所采用的技术方案是：
一种1-叔丁氧羰基哌啶-4-甲醛的制备方法，包括下列步骤：
1)将1-叔丁氧羰基-4-哌啶甲醇、有机溶剂与水混合得混合物A；
2)将步骤1)所得混合物A降温至5℃以下，加入催化剂、助催化剂和碳酸氢钠(NaHCO3)，得混合物B；所述催化剂为2,2,6,6-四甲基哌啶氧化物(TEMPO)；助催化剂为锰酸钾(K2MnO4)；
3)将步骤2)所得混合物B降温至0℃以下，加入次氯酸钠(NaClO)作为氧化剂进行氧化反应，后分离纯化，即得。
所述有机溶剂为二氯甲烷或甲苯。
混合物A中，1-叔丁氧羰基-4-哌啶甲醇与有机溶剂、水的质量比为1:(2～4):(1～2)。
优选的，步骤2)中将混合物A降温至0～5℃。
步骤2)中，催化剂、助催化剂和碳酸氢钠依次加入。
步骤2)中，所述催化剂、助催化剂的加入量为：1-叔丁氧羰基-4-哌啶甲醇与催化剂、助催化剂的质量比为1:(0.06～0.09):(0.008～0.012)。
所述碳酸氢钠的加入量为：1-叔丁氧羰基-4-哌啶甲醇与碳酸氢钠的质量比为1:(0.6～0.9)。碳酸氢钠作为碱性缓蚀剂，起提供碱性环境的作用。
优选的，步骤3)中将混合物B降温至-5～0℃。
步骤3)中，次氯酸钠的用量为：1-叔丁氧羰基-4-哌啶甲醇与次氯酸钠的质量比为1:(0.4～0.6)。所述次氯酸钠以次氯酸钠水溶液的形式加入；优选的，所述次氯酸钠水溶液的质量百分浓度为10％；1-叔丁氧羰基-4-哌啶甲醇与次氯酸钠水溶液的质量比为1:(4～6)。次氯酸钠水溶液采用滴加的方式加入体系，滴加完毕后继续搅拌进行氧化反应。氧化反应的温度不超过0℃。
在滴加次氯酸钠水溶液的过程中应保持反应体系的温度不超过0℃。次氯酸钠水溶液在20～30min内滴加完毕。
优选的，在滴加次氯酸钠水溶液的过程中应保持反应体系的温度为-5～0℃。
步骤3)中，采用薄层层析(TLC)技术进行反应监控；所用的展开剂为乙酸乙酯与石油醚的体积比为1:3的混合物。所用的吸附剂为硅胶。
优选的，次氯酸钠水溶液滴加完毕后进行氧化反应的时间为20～40min。
步骤3)中，所述分离纯化是指将体系分离水相和有机相，将所得有机相依次进行洗涤、干燥、过滤、浓缩。优选的，将所得水相用有机溶剂萃取，合并有机相，再将所得有机相依次进行洗涤、干燥、过滤、浓缩。萃取所用的有机溶剂与步骤1)所用有机溶剂保持一致，为二氯甲烷或甲苯。
所述洗涤是采用饱和食盐水洗涤；所述干燥是采用无水硫酸镁干燥。所述浓缩是在50℃条件下进行减压浓缩。
本发明的1-叔丁氧羰基哌啶-4-甲醛的制备方法，是以1-叔丁氧羰基-4-哌啶甲醇为主要原料、2,2,6,6-四甲基哌啶氧化物(TEMPO)为催化剂、锰酸钾(K2MnO4)为助催化剂、次氯酸钠(NaClO)为氧化剂，通过氧化反应并经分离纯化后得到1-叔丁氧羰基哌啶-4-甲醛产品；该制备方法所用的TEMPO-K2MnO4催化体系催化活性高、效果好、产物收率高；该方法具有操作简便、反应条件温和、易于控制、设备利用率高等优点，适合大规模工业化生产。
具体实施方式
下面结合具体实施方式对本发明作进一步的说明。
实施例1
本实施例的1-叔丁氧羰基哌啶-4-甲醛的制备方法，包括下列步骤：
1)在反应瓶中加入1-叔丁氧羰基-4-哌啶甲醇50g和二氯甲烷152g，搅拌均匀后加入65g的水，混合得混合物A；1-叔丁氧羰基-4-哌啶甲醇与二氯甲烷、水的质量比为1:3.04:1.3；
2)将步骤1)所得混合物A降温至0～5℃，依次加入4g的2,2,6,6-四甲基哌啶氧化物(TEMPO，催化剂)、0.5g的K2MnO4(助催化剂)和40g的碳酸氢钠(NaHCO3)，得混合物B；1-叔丁氧羰基-4-哌啶甲醇与TEMPO、K2MnO4、碳酸氢钠的质量比为1:0.08:0.010:0.8；
3)将步骤2)所得混合物B降温至-5～0℃，加入用滴液漏斗加入质量浓度为10％的次氯酸钠(NaClO，氧化剂)水溶液250g(1-叔丁氧羰基-4-哌啶甲醇与NaClO的质量比为1:0.5)，滴加过程中保持反应体系温度不超过0℃，滴加完毕后继续搅拌进行氧化反应30min，用TLC监控反应完毕(展开剂为乙酸乙酯与石油醚的体积比为1:3的混合物)，静置分层后分离水相和有机相，将水相用二氯甲烷萃取，合并有机相，有机相经饱和食盐水洗涤、无水硫酸镁干燥、过滤、浓缩后，得到1-叔丁氧羰基哌啶-4-甲醛产品43.1g。
经检测和计算，本实施例所得1-叔丁氧羰基哌啶-4-甲醛产品的纯度为99.5％，收率为87.0％。
实施例2
本实施例的1-叔丁氧羰基哌啶-4-甲醛的制备方法，包括下列步骤：
1)在反应器中加入1-叔丁氧羰基-4-哌啶甲醇5kg和甲苯20kg，搅拌均匀后加入10kg的水，混合得混合物A；1-叔丁氧羰基-4-哌啶甲醇与甲苯、水的质量比为1:4:2；
2)将步骤1)所得混合物A降温至0～5℃，依次加入450g的2,2,6,6-四甲基哌啶氧化物(TEMPO，催化剂)、60g的K2MnO4(助催化剂)和4.5kg的碳酸氢钠(NaHCO3)，得混合物B；1-叔丁氧羰基-4-哌啶甲醇与TEMPO、K2MnO4、碳酸氢钠的质量比为1:0.09:0.012:0.9；
3)将步骤2)所得混合物B降温至-5～0℃，加入用滴液漏斗加入质量浓度为10％的次氯酸钠(NaClO，氧化剂)水溶液21kg(1-叔丁氧羰基-4-哌啶甲醇与NaClO的质量比为1:0.42)，滴加过程中保持反应体系温度不超过0℃，滴加完毕后继续搅拌进行氧化反应30min后反应完毕，静置分层后分离水相和有机相，将水相用甲苯萃取，合并有机相，有机相经饱和食盐水洗涤、无水硫酸镁干燥、过滤、浓缩后，得到1-叔丁氧羰基哌啶-4-甲醛产品4.26kg。
经检测和计算，本实施例所得1-叔丁氧羰基哌啶-4-甲醛产品的纯度为99.3％，收率为86.1％。
实施例3
本实施例的1-叔丁氧羰基哌啶-4-甲醛的制备方法，包括下列步骤：
1)在反应瓶中加入1-叔丁氧羰基-4-哌啶甲醇75g和二氯甲烷150g，搅拌均匀后加入75g的水，混合得混合物A；1-叔丁氧羰基-4-哌啶甲醇与二氯甲烷、水的质量比为1:2:1；
2)将步骤1)所得混合物A降温至0～5℃，依次加入4.5g的2,2,6,6-四甲基哌啶氧化物(TEMPO，催化剂)、0.6g的K2MnO4(助催化剂)和45g的碳酸氢钠(NaHCO3)，得混合物B；1-叔丁氧羰基-4-哌啶甲醇与TEMPO、K2MnO4、碳酸氢钠的质量比为1:0.06:0.008:0.6；
3)将步骤2)所得混合物B降温至-5～0℃，加入用滴液漏斗加入质量浓度为10％的次氯酸钠(NaClO，氧化剂)水溶液450g(1-叔丁氧羰基-4-哌啶甲醇与NaClO的质量比为1:0.6)，滴加过程中保持反应体系温度不超过0℃，滴加完毕后继续搅拌进行氧化反应30min，用TLC监控反应完毕(展开剂为乙酸乙酯与石油醚的体积比为1:3的混合物)，静置分层后分离水相和有机相，将水相用二氯甲烷萃取，合并有机相，有机相经饱和食盐水洗涤、无水硫酸镁干燥、过滤、浓缩后，得到1-叔丁氧羰基哌啶-4-甲醛产品64.27g。
经检测和计算，本实施例所得1-叔丁氧羰基哌啶-4-甲醛产品的纯度为99.1％，收率为86.5％。
Claims (10)
1.一种1-叔丁氧羰基哌啶-4-甲醛的制备方法，其特征在于：包括下列步骤：
1)将1-叔丁氧羰基-4-哌啶甲醇、有机溶剂与水混合得混合物A；
2)将步骤1)所得混合物A降温至5℃以下，加入催化剂、助催化剂和碳酸氢钠，得混合物B；所述催化剂为2,2,6,6-四甲基哌啶氧化物；助催化剂为锰酸钾；
3)将步骤2)所得混合物B降温至0℃以下，加入次氯酸钠作为氧化剂进行氧化反应，后分离纯化，即得。
2.根据权利要求1所述的1-叔丁氧羰基哌啶-4-甲醛的制备方法，其特征在于：所述有机溶剂为二氯甲烷或甲苯。
3.根据权利要求1或2所述的1-叔丁氧羰基哌啶-4-甲醛的制备方法，其特征在于：混合物A中，1-叔丁氧羰基-4-哌啶甲醇与有机溶剂、水的质量比为1:(2～4):(1～2)。
4.根据权利要求1所述的1-叔丁氧羰基哌啶-4-甲醛的制备方法，其特征在于：步骤2)中，所述催化剂、助催化剂的加入量为：1-叔丁氧羰基-4-哌啶甲醇与催化剂、助催化剂的质量比为1:(0.06～0.09):(0.008～0.012)。
5.根据权利要求1或4所述的1-叔丁氧羰基哌啶-4-甲醛的制备方法，其特征在于：所述碳酸氢钠的加入量为：1-叔丁氧羰基-4-哌啶甲醇与碳酸氢钠的质量比为1:(0.6～0.9)。
6.根据权利要求1所述的1-叔丁氧羰基哌啶-4-甲醛的制备方法，其特征在于：步骤3)中，次氯酸钠的用量为：1-叔丁氧羰基-4-哌啶甲醇与次氯酸钠的质量比为1:(0.4～0.6)。
7.根据权利要求1所述的1-叔丁氧羰基哌啶-4-甲醛的制备方法，其特征在于：步骤3)中，采用薄层层析技术进行反应监控；所用的展开剂为乙酸乙酯与石油醚的体积比为1:3的混合物。
8.根据权利要求1或7所述的1-叔丁氧羰基哌啶-4-甲醛的制备方法，其特征在于：所述氧化反应的时间为20～40min。
9.根据权利要求1所述的1-叔丁氧羰基哌啶-4-甲醛的制备方法，其特征在于：步骤3)中，所述分离纯化是指将体系分离水相和有机相，将所得有机相依次进行洗涤、干燥、过滤、浓缩。
10.根据权利要求9所述的1-叔丁氧羰基哌啶-4-甲醛的制备方法，其特征在于：所述洗涤是采用饱和食盐水洗涤；所述干燥是采用无水硫酸镁干燥。
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| JP5274764B2 (ja) * | 2006-11-08 | 2013-08-28 | 広栄化学工業株式会社 | Ｎ−置換−ホルミルポリメチレンイミンの製造方法 |
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